DESCRIPTION: (Investigator's abstract) The hippocampal formation, consisting of the entorhinal cortex, the dentate gyrus, areas CA3 and CA1, and the subiculum, has long been considered an important component in the circuitry of declarative memory. The entorhinal cortex gives rise to the perforant path fibers, the major excitatory input to the dentate gyrus. Perforant path fibers originating in the superficial layers (II and III) of the entorhinal cortex terminate directly on areas CA3 and CA1 to make monosynaptic contacts onto the distal apical dendrites of pyramidal neurons. Very recently investigations on the direct perforant path project to area CA1 have lead to a new conceptual model of the functional organization of the hippocampal intrinsic circuitry: it has been proposed that the monosynaptic entorhinal inputs to CA3 and CA1 could provide parallel feed forward modulation of activity propagating through the trisynaptic circuitry. One obvious difficulty in evaluating the new model of parallel hippocampal functions is that the biophysical and pharmacological properties of the direct entorhinal projections to CA1 and CA3 have received little attention. The research effort made during the last grant cycle investigating the activity dependent changes in synaptic efficacy in area CA3 particularly focused on the mossy fiber synapse. As a component of the trisynaptic circuitry, the mossy fibers convey disynaptic excitation from layer II entorhinal cortical neurons to area CA3 neurons. The research proposed in this application builds upon these studies and is aimed at investigating the electrophysiological and pharmacological properties of the hitherto neglected direct, monosynaptic perforant path input to CA3 pyramidal neurons as well as its functional interaction with the mossy fiber input. This study will use in vitro hippocampal preparation in conjunction with whole-cell somatic and dendritic recordings to accomplish three major objectives: 1) To identify the electrophysiological effects of perforant path activation of CA3 pyramidal neurons. It is hypothesized that the direct perforant path monosynaptically excites CA3 pyramidal neurons via glutamatergic synapses, and disynaptically inhibits these same cells via GABAergic interneurons located in the s. lacunosum-moleculare. 2) To investigate voltage-gated conductances located in the apical dendrite of the CA3 pyramidal neuron. It is hypothesized that despite its remote dendritic location, the direct, monosynaptic perforant path input to CA3 pyramidal neurons contributes significantly to neuronal excitability via active dendritic conductances. 3) To characterize the interaction between perforant path and mossy fiber synaptic input to CA3 pyramidal cells. It is hypothesized that the reduction in somatic response to input from the direct, monosynaptic perforant path by preceding activation of mossy fibers is due to alterations of voltage-gated dendritic conductances. These pharmacological and biophysical studies will provide new insights into the functional characteristics of the direct, entorhinal input to CA3 pyramidal neurons. It also will provide a foundation for reinterpreting the intrinsic circuitry of the hippocampal formation, and its role in memory and learning function.